LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages
© 2021 Omarjee et al..
Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.
| Errataetall: |
CommentIn: Nat Rev Rheumatol. 2021 May;17(5):251. - PMID 33762710 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:218 |
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| Enthalten in: |
The Journal of experimental medicine - 218(2021), 3 vom: 01. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Omarjee, Ommar [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.09.2021 Date Revised 04.12.2021 published: Print CommentIn: Nat Rev Rheumatol. 2021 May;17(5):251. - PMID 33762710 Citation Status MEDLINE |
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| doi: |
10.1084/jem.20201006 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM321647572 |
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| 245 | 1 | 0 | |a LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages |
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| 500 | |a CommentIn: Nat Rev Rheumatol. 2021 May;17(5):251. - PMID 33762710 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 Omarjee et al. | ||
| 520 | |a Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages | ||
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